Submissions for variant NM_000530.8(MPZ):c.487G>A (p.Gly163Arg) (rs281865128)

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Total submissions: 3

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneReviews	RCV000193606	SCV000243905	pathogenic	Charcot-Marie-Tooth disease, demyelinating, type 1b	2015-03-26	no assertion criteria provided	literature only
Inherited Neuropathy Consortium	RCV000789471	SCV000928827	uncertain significance	Charcot-Marie-Tooth disease		no assertion criteria provided	literature only
Invitae	RCV000538322	SCV000636250	pathogenic	Charcot-Marie-Tooth disease, type I	2017-04-05	criteria provided, single submitter	clinical testing	This sequence change replaces glycine with arginine at codon 163 of the MPZ protein (p.Gly163Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with Charcot-Marie-Tooth type 1 (CMT1) (PMID: 8800924) as well as in three members of a family affected with CMT1 (PMID: 27088055). ClinVar contains an entry for this variant (Variation ID: 208148). A different variant (c.487G>C) giving rise to the same protein effect observed here (p.Gly163Arg) has been reported to segregate with disease in two families affected with CMT1 (PMID: 12207932, 15170620), indicating that this residue may be critical for protein function. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic.

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